There are a number of problems in medicine for which therapy requires direct physical placement of a treating agent. However, the means for achieving this end are extremely limited and this end has seemed to be extraordinarily difficult to achieve.
It is often possible to deliver a drug to a specific location, such as by the injection of local anaesthetic near a nerve which must be numbed. However, most small molecules will diffuse away from their injection site, or otherwise be removed and dispersed by the actions of the bloodstream, lymphatics and other movements of interstitial fluids. In a number of situations, it is advantageous for the therapeutic agent to remain at the desired location for a much greater length of time.
It is sometimes possible to place a bead, capsule or seed with an agent at a given location, but it is very difficult to apply such localised therapy over a surface rather than at a single point. Ideally there should be a rapid and effective means for coating certain surfaces in the human body with therapeutic agents.
One such problem, well known to surgeons who specialise in the treatment of brain cancer (e.g. gliomas), arises because tumour cells infiltrate into the otherwise normal brain surrounding a gross tumour. The gross bulk of tumour is removed surgically by craniotomy, however the margins of apparently normal brain always contain sufficient numbers of tumour cells as to make local recurrence of the tumour a virtual certainty. These tumours do not metastasise, so local recurrence is generally the only type of recurrence to be expected.
To treat the small number of remaining cancer cells, chemotherapy can be given. However, even very toxic agents which cause severe toxic side-effects throughout the body have only a very slight slowing effect on tumour cell growth of gliomas. Radiation therapy may be given but, in young children, the radiation causes grievous harm to the surrounding brain and, in adults as well, there is risk of severe scarring from the radiation which can cause swelling and mass effects in large regions of the brain. Although radiation clearly slows the growth of the tumour, it is virtually impossible to deliver enough radiation to slow the tumour substantially without causing unacceptable damage to the brain. Results for treatment of brain cancer remain dismal, and life expectancy after diagnosis is measured in months with or without surgery.
One significant recent advance comes from improved methods of applying ‘brachytherapy’. In some brachytherapy approaches, multiple hollow latex catheters with radioactive material in their tips are inserted into the brain, generally with computer and image-guided stereotactic methodology or by use of any one of a number of computer and image-guided spatial position wands. These catheters cause a risk of infection spreading along the catheter and do not provide a uniform field of radiation and are not well suited for treating the surface of the tumour resection bed in the brain.
In one improvement which is currently the best state of the art, the radioactive material, commonly an isotope of iodine, is enclosed in small stainless steel or titanium ‘seeds’ which are 0.8 mm×4.5 mm in size. Immediately after the surgeon resects the tumour, and before any surgical closure is commenced, the surgeon uses a tissue adhesive such as a cyanoacrylate-based glue to attach the seeds to the brain surface along the plane of tumour resection. A tumour which was 4 cm in diameter has a surface area of e.g. 30-40 cm2 of resection bed and may require some eighty or ninety individual seeds to be glued in place, one by one, in a grid pattern with as regular a spacing as possible. Each seed has a radioactive source which treats a surrounding sphere with low level, low penetration energy for use over a long period of time until the radiation decays away over, e.g. 3-4 months. The seeds are left in place.
The problem with this current method is that the painstaking process of gluing on the seeds requires as much as an hour during which time the full operating room team (surgeon, assistant surgeon, radiation therapy treatment planner, radiation therapy technician, anaesthesiologist, scrub nurse, circulating nurse) are all required to be present and are all subject to unshielded radiation exposure.
An alternative type of glue for surgical use is termed a ‘tissue glue’. This is a natural biological material that takes advantage of natural components of the human clotting system. The clotting proteins and cofactors are either extracted from donor blood, or extracted from the patient's own blood prior to surgery, or, in many cases now, extracted from the patient's own blood during the surgery itself. Typically, the glue is maintained in two components, one with fibrin protein solution and the other with e.g. the calcium solution which helps activate the clotting cascade. The two components are loaded into two separate syringes and the needle tips from the two syringes are bent to run parallel to each other so that the two tips are closely apposed. The surgeon uses a double syringe apparatus to apply the two fluids to the surface of interest simultaneously. As the two fluids emerge from the needle tips onto the tissue surface they mix and congeal. This material is used for plugging leaks in the dura membranes around the brain in order to prevent leakage of spinal fluid as well as for a wide variety of other surgical applications including the assistance of wound closure and haemostasis. Tissue glues have also been proposed as means of achieving slow controlled release of various growth factors and antibiotics.
It is not possible to suspend the seeds in either a liquid cyanoacrylate glue or in either component of a tissue glue as described above, because they would sink out of solution. It would be possible to include a variety of radioactive metal cations in chelate molecules and then dissolve these molecules in a tissue glue component; however, even for very large proteins, the tissue glue allows migration of the molecules through its interstices. Thus from the point of view of most molecules, the glue is not a glue at all, but only a matrix through which they can diffuse along with the tissue water in which they are dissolved.